Purpose: To assess the effects of combining the TLR agonist activity of PSK to HER-2/neu (HER2) directed monoclonel antibody therapy using a HER2 specific vaccine for the treatment of patients with advanced stage breast cancer. We will conduct pre-clinical gene-signature biomarker work in year 1 and 2 then conduct a placebo-controlled phase II randomized controlled clinical trial in years 3 and 4. Hypothesis: PSK, when added to a HER2 vaccine will improve immune response and Survival in women with advanced HER2 overexpressing breast cancer. Methods: 1) Determine whether PSK administered concurrently with HER2-targeted vaccine can enhance tumor antigen-specific immune response and prevent or delay disease progression in neu-transgenic mice; 2) Identify a gene signature that predicts clinical response in neu-transgenic mice receiving PSK, trastuzumab, and a HER2-tergeted vaccine; and 3) Determine the safety and immunogenicity of PSK as a component of combination immunotherapy in patients with advanced stage (stage IV) breast cancer. Clinical Trial Design: 30 women with advenced HER-2/neu overexpressing breast cancer who receive trastuzumab + HER2 peptide vaccine therapy will be randomized to receive PSK or placebo orally (3000 mg/day) concomitant with vaccine therapy. Primary endpoints will be intermolecular epitope spreading, changes in TGF-b serum levels and peripheral blood biomarkers identified in neu-transgenic mice as predictive of clinical response in breast cancer patients receiving HER2 ICD vaccine. PUBLIC HEALTH RELEVANCE: Trametes versicolor is an immunologically active medicinal mushroom that is likely to improve the effectiveness of treatments for women with advanced breast cancer. We will investigate the effect of oral doses of PSK, a T. versicolor extract prescribed in Japan as a cancer drug, in augmenting the anticancer immune response in advanced breast cancer.